The present invention relates to the preparation of camptothecin and of its derivatives. It relates more particularly to the preparation of camptothecin, of topotecan and of irinotecan.
Camptothecin derivatives of general formula: 
in which in particular R1 is hydrogen, halogen or alkyl and X is a chlorine atom or NR2R3 for which R2 and R3, which are identical or different, can represent a hydrogen atom, an optionally substituted alkyl radical, an optionally substituted carbocyclyl, an optionally substituted heterocycle or alkyl radicals (optionally substituted) which form, with the nitrogen atom to which they are attached, a heterocycle optionally comprising another heteroatom chosen from O, S and/or NR4, R4 being a hydrogen atom or an alkyl radical, and in which the Xxe2x80x94COxe2x80x94Oxe2x80x94 group is situated at the 9-, 10- or 11-position of the A ring are known according to European Patent EP 137 145, cited here by way of reference. These camptothecin derivatives are anticancer agents which are topoisomerase I inhibitors, among which irinotecan, for which Xxe2x80x94COxe2x80x94Oxe2x80x94 is [4-(1-piperidino)-1-piperidino]carbonyloxy, is an active principle which is particularly effective with respect to solid tumours and in particular colorectal cancer.
Other camptothecin derivatives which are mentioned as anticancer agents, in particular derivatives with a structure analogous to the structure given above, in which structure Xxe2x80x94COxe2x80x94Oxe2x80x94 is replaced by an xe2x80x94Xxe2x80x2Rxe2x80x2 radical for which Xxe2x80x2 is O or S and Rxe2x80x2 is a hydrogen atom or an alkyl or acyl radical, are also known according to Patent Application EP 74 256, cited here by way of reference.
Other camptothecin derivatives have also been disclosed, for example in the patents or patent applications, cited here by way of reference, EP 56 692, EP 88 642, EP 296 612, EP 321 122, EP 325 247, EP 540 099, EP 737 686, WO 9003169, WO 9637496, WO 9638146, WO 9638449, WO 9700876, U.S. Pat. No. 7,104,894, JP 57 116015, JP 57 116074, JP 59 005188, JP 60 019790, JP 01 249777, JP 01246287 or JP 91 012070, or in Canc. Res., 38 (1997) Abst. 1526 or 95 (San Diego, April 12-16), Canc. Res., 55(3), 603-609 (1995) or AFMC Int. Med. Chem. Symp. (1997) Abst. PB-55 (Seoul, July 27-August 1).
Irinotecan (CPT-11) and its derivatives are usually prepared from natural camptothecin (U.S. Pat. No. 4,604,463; S. Sawada et al., Chem. Pharm. Bull., 39, 2574-80 (1991), Chem. Pharm. Bull., 39, 1446-54 (1991), Chem. Pharm. Bull., 39, 3183-88 (1991) and Ann. N.Y. Acad. Sci., 803, 13-28 (1996). The stages comprise the introduction of a hydroxyl functional group at the 9-position, an alkylation at the 11-position and the introduction of a radical at the 9-position.
International Patent Application WO 96/31513 has disclosed the preparation of mappicine and camptothecin derivatives by total synthesis by firstly preparing the C-D or C-D-E ring sequence.
Tetrahedron, 53(32), 11049-60 (1997), also describes total syntheses of camptothecin derivatives in which the A-B and D-E rings are prepared beforehand or, according to another aspect, the C-D-E or A-B-C sequences.
It has now been found, and it this which forms the subject matter of the present invention, that camptothecin or camptothecin derivatives of following formula (I): 
in which R1, R2 and R3 each represent an identical or different group chosen from:
hydrogen,
a hydroxyl group,
a halogen atom chosen from fluorine, chlorine, bromine or iodine,
linear or branched alkoxy groups comprising 1 to 4 carbon atoms,
linear or branched alkylthio groups comprising 1 to 4 carbon atoms,
(C1-C4)alkylamino groups optionally substituted by one or more C1-C4 alkyl groups,
aralkyl groups optionally substituted by a C1-C4 alkyl group, said aryl groups also optionally being heterocycles comprising 1 to 3 heteroatoms chosen from oxygen, sulfur and nitrogen,
arylcarbonyloxy groups, said aryl groups also optionally being mono- or polycyclic heterocycles comprising 1 to 3 heteroatoms chosen from oxygen, sulfur and nitrogen, can be obtained by a convergent synthesis starting from a 3-(aminomethyl)quinoline derivative and 5-hydroxy-5-ethyl-6-oxo-5,6-dihydropyrancarboxylic acid with particularly advantageous results.
The preferred and commercial compounds synthesized by the process of the invention are:
camptothecin, for which R1, R2 and R3 represent hydrogen,
topotecan or Hycamtin(copyright), for which R1 is hydrogen, R2 represents a dimethylamino-methyl group and R3 represents a hydroxyl group,
irinotecan or Campto(copyright), for which R1 represents an ethyl group, R2 represents a piperidinopiperidinocarbonyloxy group and R3 represents hydrogen.
The process according to the invention consists in condensing a 3-(aminomethyl)quinoline derivative and 5-hydroxy-5-ethyl-6-oxo-5,6-dihydro-pyrancarboxylic acid, followed by an ethynylation stage, optionally by a hydrolysis stage, by a double cyclization stage, by a dehydrogenation and by a deprotection/dealkoxycarbonylation stage.
According to the invention, 5-hydroxy-5-ethyl-6-oxo-5,6-dihydropyrancarboxylic acid with the structure: 
in which G1, represents hydrogen or a protective group for the hydroxyl functional group chosen in particular from the benzyl, para-methoxybenzyl, methoxymethyl, tert-butyl and trialkylsilyl groups, at least one alkyl group in the trialkylsilyl having more than two carbon atoms, is condensed with a 3-(aminomethyl)quinoline derivative of general formula: 
in which R1, R2 and R3 have the same meaning as in the formula (I) or represent protected radicals or radicals which can be easily converted to R1, R2 and R3 radicals mentioned above and Y represents a leaving group chosen in particular from halogen atoms or an OSO2R radical where R represents an alkyl, tolyl, naphthyl or trifluoromethyl group, in order to obtain the quinoline derivative of general formula: 
in which G1, R1, R2, R3 and Y are defined as above.
The benzyl group is preferred among the G1 groups. Preference is given, among the Y groups, to halogens chosen from bromine or iodine and, among the OSO2R groups, to trifluoromethylsulfonate.
The reaction is generally carried out according to the usual methods for condensing acids with amines, in particular by reaction with the acid or a reactive or activated derivative of the acid.
When the condensation of a reactive derivative of the acid of general formula (II) is carried out, the reaction is advantageously carried out by means of the acid chloride, of the anhydride, of a mixed anhydride or of a reactive ester, or of an ammonium or pyridinium acyl intermediate.
It is preferable, among the reaction conditions, to use a temperature of between xe2x88x9240 and +40xc2x0 C. It is preferable, among the inert solvents which can be used, to use an organic solvent such as in particular a chlorinated solvent (dichloromethane, dichloroethane or chloroform, for example). The reaction can optionally be carried out in the presence of an acid acceptor, such as a nitrogenous organic base, such as, for example, pyridine, dimethyl-aminopyridine, N-methylmorpholine or a trialkylamine (in particular triethylamine or diisopropylethylamine). It is also preferable to carry out the reaction in the presence of a coupling agent, such as a carbodiimide [for example dicyclohexylcarbodiimide or 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide], N,Nxe2x80x2-carbonyldiimidazole or 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline. The reaction is preferably carried out under argon or nitrogen.
It is understood that the amino, alkylamino or carboxyl radicals present in R1, R2 and R3, like the hydroxyl functional group carried by the pyran ring, are preferably protected beforehand. Protection is carried out in particular according to the methods described by T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis (3rd ed.), A. Wiley-Interscience Publication (1999).
Subsequently, the quinoline derivative of general formula (IV) and trialkyl (optionally substituted C1-C4) orthopropiolate or alkyl (optionally substituted C1-C4) propiolate are reacted in the presence of a palladium complex [such as, for example, tris(dibenzylideneacetone)dipalladium, bis(benzo-nitrile)palladium chloride or dichlorobis(triphenyl-phosphine)palladium] and of copper iodide and of a base, such as a tertiary amine (trialkylamine) or of an alkaline carbonate, to give the quinoline derivative of general formula: 
in which R1, R2, R3 and G1 are defined as above and Alk represents a C1-C4 alkyl group optionally substituted by an aryl or heteroaryl group.
When the condensation is carried out in the presence of trialkyl (optionally substituted C1-C4) orthopropiolate, a hydrolysis stage is carried out after the condensation stage.
The condensation reaction is preferably carried out in an inert organic solvent, such as an ether (dioxane, for example), or in an amide, such as acetamide or dimethylformamide, at a temperature of between 20 and 110xc2x0 C. This temperature is preferably between 20 and 80xc2x0 C. and the reaction is carried out under argon or nitrogen.
The quinoline derivative of general formula (V) is subsequently cyclized by addition of a base, preferably in the presence of DBU (1,8-diazabicyclo[5.40]undec-7-ene) or of DBN (1,5-diazabicyclo[5.4.0]non-5-ene or of DABCO (1,4-diazabicyclo[2.2.2]octane, to give the tetracyclic derivative of general formula (VI): 
in which Alk, R1, R2, R3 and G1 are defined as above.
As regards the reaction conditions, the reaction is preferably carried out in an anhydrous medium, in an inert organic solvent, such as an aromatic solvent (for example toluene), at a temperature of between xe2x88x9230 and +30xc2x0 C. The reaction is preferably carried out under argon or under nitrogen.
This derivative is subsequently subjected to a cyclization to give the ester of protected camptothecin and/or of its derivatives of general formula: 
in which R1, R2, R3, Alk and G1 are defined as above.
The cyclization is preferably carried out by irradiation. The irradiation is carried out alone, in the presence of an oxidizing agent, such as iodine, or with a reducing agent, such as a borohydride.
The irradiation is generally carried out in an organic solvent chosen in particular from halogenated aliphatic solvents (for example, dichloromethane or chloroform), in the first two cases mentioned above, or an alcohol (for example methanol), for the final case mentioned above, at a temperature preferably of between xe2x88x9230xc2x0 C. and 50xc2x0 C.
The derivative of formula (VII) above which does not have a double bond either on the lactone or on the piperidone and where Alk is a methyl group substituted by an aryl or heteroaryl group is subsequently hydrogenated in the presence of a palladium catalyst to give the acid, which is converted to camptothecin and/or its derivatives by the action of palladium and cymene at high temperature, optionally followed by a deprotection of the hydroxyl group on the lactone.
The derivative of formula (VII) above which has one double bond or optionally none on the piperidone can be treated with DDQ (dichlorodicyanobenzoquinone) to give the compound of formula (VII) with the two double bonds.
The derivative of general formula (VII) having two double bonds on the lactone and on the piperidone ring is finally deprotected and dealkoxycarbonylated by the action of hydrobromic acid at a temperature of between 50 and 140xc2x0 C., to give camptothecin or its derivatives of general formula (I): 
The 3-(aminomethyl)quinoline derivative of general formula (III) in which R1, R2, R3 and Y are defined as above can be prepared by reduction of the corresponding 3-(azidomethyl)quinoline derivative of general formula: 
in which R1, R2, R3 and Y are defined as above.
The reduction is carried out, for example, by catalytic hydrogenation in the presence of platinum oxide in an alcoholic medium (for example, ethanol or methanol) at a temperature of between 0 and 30xc2x0 C.
The 3-(azidomethyl)quinoline derivative of general formula (VIII) is prepared from the 3-methyl-quinoline derivative of general formula: 
in which R1, R2, R3 and Y are defined as above, the Y groups being identical or different.
The reaction is generally carried out by reaction with sodium azide in an organic solvent, such as an amide (for example dimethylformamide), at a temperature in the region of 20xc2x0 C. The reaction is preferably carried out under argon or under nitrogen.
5-Hydroxy-5-ethyl-6-oxo-5,6-dihydropyran-carboxylic acid of formula (II) is prepared from the C1-C4 alkyl (Alk1) ester of 2-hydroxybutyric acid, the hydroxyl functional group of which is protected, by condensation with a compound of formula (X) in which Alk2 represents a C1-C4 alkyl group 
to give the compound of following formula (XI) 
in the presence of a strong base, such as an alkyllithium, LDA, alkaline hexamethyldisilazide (for example lithium hexamethyldisilazide) or alkaline tetramethylpiperidide (for example lithium tetramethylpiperidide), in an inert solvent (for example an ether, such as tetrahydrofuran).
The reaction is maintained in particular between xe2x88x9280 and xe2x88x9240xc2x0 C.
The cyclization of the compound of formula (XI) is carried out in particular to the compound of following formula (XII): 
in which G1 represents a hydrogen atom or a protective group for the alcohol functional group, in the presence of a base, such as an alkaline hydroxide or an alkaline alkoxide (for example, lithium hydroxide or sodium ethoxide), in an inert solvent, such as an ether or an alcohol, at a temperature of in particular between 0 and 40xc2x0 C. When the base used is an alkaline hydroxide, the saponification of the ester is carried out simultaneously; when the base used is an alkaline alkoxide, the saponification of the ester is carried out subsequently, in particular in the presence of an alkaline hydroxide. Finally, the compound is resolved according to methods known to a person skilled in the art.
The compound of formula (X) is prepared according to, for example, the protocol described by Ben Ayed, Amri and El Gaied in Tetrahedron, 1991, 47, p. 9621-9628.
The products obtained according to the process, camptothecin and its derivatives, can be purified according to the usual methods used by a person skilled in the art. For example by chromatography.
Camptothecin derivatives are usually administered by the injectable route, more particularly by the intravenous route, in the form of a sterile solution or of an emulsion. Camptothecin derivatives can also be administered by the oral route, in the form of solid or liquid compositions.
When the camptothecin derivative is administered by the intravenous route, these compositions can also comprise adjuvants, in particular wetting, isotonizing, emulsifying, dispersing and stabilizing agents. Irinotecan (CPT-11) is in particular administered in solution in a medium for intravenous injection, at doses of between 175 to 500 mg/m2.
The products of formula III, IV, V, VI, VII, VIII, XI and XII are claimed individually as novel intermediates.
The following examples, given without implying limitation, illustrate the present invention.